Bottom Line:
One of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance.Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media.We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied.

ABSTRACTOne of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance. Essential genes, whose knockout leads to a lethal phenotype are considered of high functional importance, yet whether they are truly more conserved than nonessential genes has been the topic of much debate, fuelled by a host of contradictory findings. Here we conduct the first large-scale study utilizing genome-scale metabolic modeling and spanning many bacterial species, which aims to answer this question. Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media. We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied. The results show that bacteria do exhibit an overall tendency for differential conservation of their essential genes vs. their non-essential ones, yet this tendency is highly variable across species. We show that the model bacterium E. coli K12 may or may not exhibit differential conservation of essential genes depending on its growth medium, shedding light on previous experimental studies showing opposite trends.

pone.0123785.g003: Metabolic model KOR class distribution.The distribution of metabolic models among KOR classes: The (normally-fitted) distribution tends towards the Strongly-KOR class, showing an overall mild tendency of the bacteria studied to conserve the sequence of their essential genes. No bacterial models were found to be Strongly-anti-KOR.

Mentions:
Fig 2 shows the resulting KOR score intervals for the 69 bacteria models surveyed, and Fig 3 shows the distribution of metabolic models among the 5 KOR classes. Four models were found to be strongly KOR, while no models were found to be strongly anti-KOR; fitting a normal distribution to the number of models in the 5 classes shows the mean to lie between Weakly KOR and Undecided, supporting the notion that bacteria tend to follow the KOR hypothesis, albeit weakly. 24 models were classified as Weakly KOR, meaning that these bacteria may comply with the KOR hypothesis according to essential genes found on some lab media, but will not follow the KOR hypotheses when tested on other media. Regarding E.coli K12, one model was classified as Weakly KOR and the other as Undecided, implying that experimentally determining whether E.coli follows the KOR Hypothesis or not is media dependent. This may account for several contradicting previous studies which targeted the KOR score of this bacterium [1], [9], [10]. A metabolic model of S. cerevisiae [27] was analyzed in the same manner and was classified as Weakly KOR, which again may explain previous inconsistent findings with regards to this yeast [4]–[8]. Several bacterial models occupy the Weakly anti-KOR class, meaning that on certain media their nonessential genes are significantly conserved compared to their essential genes—the complete opposite of the KOR hypothesis. We did not find an organism whose essential genes were differentially conserved in some medium and its nonessential genes were differentially conserved in another medium, even though this is theoretically possible.

pone.0123785.g003: Metabolic model KOR class distribution.The distribution of metabolic models among KOR classes: The (normally-fitted) distribution tends towards the Strongly-KOR class, showing an overall mild tendency of the bacteria studied to conserve the sequence of their essential genes. No bacterial models were found to be Strongly-anti-KOR.

Mentions:
Fig 2 shows the resulting KOR score intervals for the 69 bacteria models surveyed, and Fig 3 shows the distribution of metabolic models among the 5 KOR classes. Four models were found to be strongly KOR, while no models were found to be strongly anti-KOR; fitting a normal distribution to the number of models in the 5 classes shows the mean to lie between Weakly KOR and Undecided, supporting the notion that bacteria tend to follow the KOR hypothesis, albeit weakly. 24 models were classified as Weakly KOR, meaning that these bacteria may comply with the KOR hypothesis according to essential genes found on some lab media, but will not follow the KOR hypotheses when tested on other media. Regarding E.coli K12, one model was classified as Weakly KOR and the other as Undecided, implying that experimentally determining whether E.coli follows the KOR Hypothesis or not is media dependent. This may account for several contradicting previous studies which targeted the KOR score of this bacterium [1], [9], [10]. A metabolic model of S. cerevisiae [27] was analyzed in the same manner and was classified as Weakly KOR, which again may explain previous inconsistent findings with regards to this yeast [4]–[8]. Several bacterial models occupy the Weakly anti-KOR class, meaning that on certain media their nonessential genes are significantly conserved compared to their essential genes—the complete opposite of the KOR hypothesis. We did not find an organism whose essential genes were differentially conserved in some medium and its nonessential genes were differentially conserved in another medium, even though this is theoretically possible.

Bottom Line:
One of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance.Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media.We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied.

ABSTRACTOne of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance. Essential genes, whose knockout leads to a lethal phenotype are considered of high functional importance, yet whether they are truly more conserved than nonessential genes has been the topic of much debate, fuelled by a host of contradictory findings. Here we conduct the first large-scale study utilizing genome-scale metabolic modeling and spanning many bacterial species, which aims to answer this question. Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media. We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied. The results show that bacteria do exhibit an overall tendency for differential conservation of their essential genes vs. their non-essential ones, yet this tendency is highly variable across species. We show that the model bacterium E. coli K12 may or may not exhibit differential conservation of essential genes depending on its growth medium, shedding light on previous experimental studies showing opposite trends.